N-benzenesulfonyl-L-proline derivatives, method for preparing and therapeutic use

ABSTRACT

The present invention relates to compounds selected from the group consisting of 
     (i) the compounds of formula I: ##STR1## in which: X is a halogen atom or a methyl group, 
     A is a group --N(R 3 )CO-- or --CO--N(R 3 )--, 
     B is a single bond, --CH 2  -- or --CH 2  --O--, 
     R 1  is H, a C 1  -C 3  alkyl group or a CF 3  group, 
     R 2  and R 3  are each independently H or a C 1  -C 3  alkyl group, 
     W is CH or N, and 
     n is 2, 3, 4 or 5; and 
     (ii) their addition salts. 
     It further relates to the process for their preparation and to their use in therapeutics, especially for combating pathological conditions involving bradykinin.

FIELD OF THE INVENTION

The present invention relates to novel compounds derived fromN-(benzenesulfonyl)-(L)-proline, to the process for their preparationand to their use in therapeutics.

These novel compounds have an antagonistic action towards bradykinin andare useful in therapeutics, particularly for the treatment of pain andinflammation and especially for the treatment of asthma, cerebraltraumatic shock and allergic rhinitis.

PRIOR ART

It is known that one of the possible treatments for certain pathologicalconditions of a painful and/or inflammatory nature (such as asthma,rhinitis, septic shock, toothache, etc.) is to inhibit the action ofcertain hormones such as bradykinin or kallidin. These peptide hormonesare in fact involved in a large number of physiological processes, someof which are closely associated with these pathological conditions.

Although no product possessing this mode of action has yet beenmarketed, numerous studies have been undertaken in order to understandthe mode of action of kinins, particularly bradykinin and its homologs,and then to create compounds capable of antagonizing the bradykininreceptors. Pharmacological Reviews vol. 44 no. 1, pages 1-80 (1992) andBiopolymers (Peptide Science) vol. 37, pages 143-155 (1995) may be citedamong the numerous publications reporting this work.

Bradykinin is a peptide hormone consisting of 9 amino acids(Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) and kallidin is a peptide hormone(Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) which contains an additionalamino acid (Lys) compared with bradykinin. It is known that earlierstudies made it possible to obtain peptides which interact with thebradykinin receptors: some of them, like bradycor (CP.0127 fromCORTECH), icatibant (HOE 140 from HOECHST) ["bradycor" and "icatibant"are international non-proprietary names (INN)] or NPC 17761 (fromSCIOS-NOVA), have an inhibitory action on the binding of bradykinin toits B₂ receptor. More recently, non-peptide compounds have been proposedas antagonists towards the binding of bradykinin to its B₂ receptor,especially in EP-A-0596406 and EP-A-0622361. It is also known thatcertain compounds which are structurally related to the compoundsreferred to in the two patent applications cited above have already beendescribed for their possible antithrombotic properties, especially inthe publications DE-A-3617183 and EP-A-0261539.

OBJECT OF THE INVENTION

There is a need for reducing or eliminating pain and inflammation inmammals and particularly in man.

To meet this need, a novel technical solution has been sought which iseffective in the treatment of pain, irrespective of its origin, andespecially in the treatment of (i) pain associated with inflammatoryphenomena, and (ii) inflammation.

According to the invention, it is proposed to provide a novel technicalsolution which involves competitive binding, at the bradykinin B₂receptor, between (i) bradykinin and related or analogous hormones, and(ii) an antagonist, and utilizes compounds of the benzenesulfonamidetype which are structurally different from the known products mentionedabove and which are capable of limiting or substantially inhibiting thebinding of bradykinin and analogous hormones to said bradykinin B₂receptor.

According to this technical solution, the novel compounds bindcompetitively to the bradykinin B₂ receptor without causing the effectsof bradykinin on this receptor (the substance is said to be anantagonist). This results in the appearance of a state analogous to thatobserved in the absence of bradykinin, namely a reduction in pain andinflammatory reactions.

According to this novel technical solution, it is proposed according toa first aspect of the invention to provide compounds derived fromN-(benzenesulfonyl)-(L)-proline as novel industrial products, accordingto a second aspect of the invention to provide a process for thepreparation of these compounds, and according to a third aspect of theinvention to provide the use of these compounds, especially intherapeutics, as analgesics and/or anti-inflammatories.

SUBJECT OF THE INVENTION

According to the novel technical solution of the invention, anN-(benzenesulfonyl)-L-proline compound is recommended as a novelindustrial product, said compound being selected from the groupconsisting of:

(i) the compounds of formula I: ##STR2## in which:

X is a halogen atom or a methyl group,

A is a group --N(R₃)--CO-- or --CO--N(R₃)--,

B is a single bond, --CH₂ -- or --CH₂ --O--,

R₁ is a hydrogen atom, a C₁ -C₃ alkyl group with a linear or branchedhydrocarbon chain, or a trifluoromethyl group,

R₂ and R₃ are each independently a hydrogen atom or a C₁ -C₃ alkyl groupwith a linear or branched hydrocarbon chain,

W is CH (in which case the aromatic ring is a phenyl group) or N (inwhich case the aromatic ring is a pyridinyl group), and

n is 2, 3, 4 or 5; and

(ii) their addition salts.

According to the invention, a process for the preparation of thecompounds of formula I and their addition salts is also recommended.

The use of an antagonist of a receptor of bradykinin and hormonesanalogous to bradykinin is also recommended, wherein a bradykinin B₂receptor antagonist selected from the compounds of formula I and theirnon-toxic addition salts is used to obtain a drug intended for use intherapeutics to combat pathological conditions involving bradykinin orits analogs, in particular to combat pain, and especially in thetreatment or prevention of pathological conditions associated withinflammatory or painfull states.

DETAILED DESCRIPTION OF THE INVENTION

In general formula I of the compounds of the invention, halogen atom isunderstood as meaning a fluorine, chlorine, bromine or iodine atom, thepreferred halogen being the chlorine atom.

C₁ -C₃ alkyl group with a linear or branched hydrocarbon chain isunderstood here as meaning the methyl, ethyl, propyl or 1-methylethylgroup.

In the compound of formula I, the nitrogen heterocycle of thepyrrolidine type comprises 1 asymmetric carbon atom. According to theinvention, this carbon has the S configuration, which corresponds to theconfiguration of L-proline.

As indicated in the general formula of the compounds according to theinvention, the structure comprises an amidine group, --C(═NH)NH₂, on anaromatic ring; this amidine group can occupy any substitutable positionon its aromatic ring; in particular, it can be located in the 2-, 3- or4-position if said ring is phenyl, or in the 3-, 4-, 5- or 6-position ifsaid ring is pyridinyl.

"Addition salts" are understood as meaning the acid addition saltsobtained by reacting a compound of formula I with a mineral acid or anorganic acid. The preferred mineral acids for salifying a basic compoundof formula I are hydrochloric, hydrobromic, phosphoric and sulfuricacids. The preferred organic acids for salifying a basic compound offormula I are methanesulfonic, benzenesulfonic, maleic, fumaric, oxalic,citric, lactic and trifluoroacetic acids.

The general process recommended according to the invention for thepreparation of the compounds of formula I comprises the steps whichconsist in:

(1) reacting an acid of formula II: ##STR3## in which:

R₁ is a hydrogen atom, a C₁ -C₃ alkyl group with a linear or branchedhydrocarbon chain, or a trifluoromethyl group, and

X is a halogen or a methyl group,

with an amine of formula III: ##STR4## in which:

R₂ and R₃ are each independently a hydrogen atom or a C₁ -C₃ alkylgroup, n is 2, 3, 4 or 5, and

Y is an amino-protecting group, for example the group Boc(1,1-dimethylethoxycarbonyl), in a solvent, for example dichloromethaneor dimethylformamide, in the presence of at least one activator commonlyused to create linkages of the peptide types, for example(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and1-hydroxy-7-azabenzotriazole (HOAT), at a temperature near roomtemperature (i.e. a temperature of between about 0 and about 40° C. andpreferably a temperature of between 10 and 35° C.), for 2 to 50 hours,to give a compound of formula (IV): ##STR5## in which R₁, R₂, R₃, X, Yand n are as defined above; (2) deprotecting the resulting compound offormula IV so as to replace the protecting group Y with a hydrogen atom,for example, if Y is the group Boc, by reacting the compound of formulaIV with trifluoroacetic acid in a solvent such as dichloromethane orethyl acetate, at room temperature (15-25° C.), for 5 to 30 hours, togive the compound of formula V: ##STR6## in which R₁, R₂, R₃, X and nare as defined above; (as a variant of this process, the group Boc canbe replaced by reaction with aqueous hydrochloric acid solution, thecompound of formula IV being allowed to react for 1 to 10 hours at atemperature of between 30 and 60° C., in which case the compound offormula V is obtained in the form of the dihydrochloride); and

(3) reacting the resulting compound of formula V with an acid of formulaVI: ##STR7## in which:

B is a single bond or a group --CH₂ -- or --CH₂ --O--, and

W is --CH-- or N,

under conditions analogous to those recommended for step (1) above, and,if necessary, in the presence of a base such as N-methylmorpholine ifthe amine of formula V is reacted in its salified form, to give thecompound of formula I: ##STR8## in which:

A is --N(R₃)--CO--,

B is a single bond, --CH₂ -- or --CH₂ --O--,

R₁ is a hydrogen atom, a C₁ -C₃ alkyl group or a trifluoromethyl group,

R₂ and R₃ are each independently H or a C₁ -C₃ alkyl group,

X is a halogen or a methyl group,

W is CH or N, and

n is 2, 3, 4 or 5.

In a first variant, A, the compound of formula I (in which A is--N(R₃)--CO--) can be obtained by reacting a compound of formula V,obtained according to step (2) above, with an acid chloride of formulaVII: ##STR9## in which:

B is a single bond, --CH₂ -- or --CH₂ --O--, and

W is CH or N, in a solvent, for example dichloromethane, and in thepresence of an aprotic base, for example N-methylmorpholine, at atemperature near room temperature, for 2 to 30 hours.

In a second variant, called B, (a) the compound of formula V, obtainedin step (2) above, is reacted with a compound of formula VIII: ##STR10##in which:

B is a single bond, --CH₂ -- or --CH₂ O--, and

W is CH or N,

under operating conditions analogous to those of step (3) describedabove, to give a compound of formula IX: ##STR11## in which R₁, R₂, R₃,X, W, n and B are as defined in the starting materials; (b) theresulting compound of formula IX is reacted with hydroxylamine (freedfrom its hydrochloride in the reaction medium by reaction with a basesuch as triethylamine), in a solvent, for example dimethyl sulfoxide(DMSO), at room temperature, for 2 to 12 hours, to give the compound offormula X: ##STR12## in which R₁, R₂, R₃, X, W, n and B are as definedabove; (c) the resulting compound of formula X is reacted with excessacetic anhydride in a solvent, for example dichloromethane, at roomtemperature, for 1 to 15 hours, to give the compound of formula XI:##STR13## in which R₁, R₂, R₃, X, W, n and B are as defined above; and(d) the resulting compound of formula XI is catalytically hydrogenatedin a solvent, for example methanol, in the presence of a hydrogenationcatalyst such as Lindlar's catalyst, at room temperature, under ahydrogen pressure of between 10⁵ and 5.10⁵ Pa, to give the compound offormula I in which R₁, R₂, R₃, X, W, n and B are as defined above, A isthe group --N(R₃)--CO-- and the amidine group retains the initialposition of the cyano group of the starting acid.

In a third variant, called C, of the process for the preparation of acompound according to the invention, it is recommended to (α) react anacid of formula II: ##STR14## in which:

R₁ is a hydrogen atom, a C₁ -C₃ alkyl group with a linear or branchedhydrocarbon chain, or the trifluoromethyl group, and

X is a halogen or the methyl group,

with an amine of formula XII: ##STR15## in which:

A is a group --N(R₃)--CO-- or a group --CO--N(R₃)--,

B is a single bond, --CH₂ -- or --CH₂ --O--,

R₂ and R₃ are each independently H or a C₁ -C₃ alkyl group,

n is 2, 3, 4 or 5, and

W is CH or a nitrogen atom,

under conditions analogous to those described above in step (1) of thegeneral process, to give a compound of formula IXa: ##STR16## in whichA, B, R₁, R₂, R₃, X, W and n are as defined in the starting materials;and (β) carry out the steps analogous to those described above invariant B to give the compound of formula I from the compound of formulaIXa by conversion of the cyano group to an amidine group.

If necessary, the compound of formula I, normally obtained in the formof the free base according to the above procedures, can be converted toone of its salts with an acid by reaction with said acid, generally inexcess and in solution in a solvent.

The invention will be understood more clearly from the followingPreparatory Examples and the results of pharmacological tests obtainedwith compounds according to the invention.

Of course, these details as a whole do not imply a limitation but aregiven by way of illustration.

In the case of compounds which have an asymmetric carbon in theirstructure, the absence of a particular indication, or the notation(R,S), means that the compounds are racemic; in the case of compoundswhich exhibit chirality, this is indicated immediately after thenumbering of the substituent carried by said asymmetric carbon; thesymbol (R) or (S) is then used in accordance with the Cahn-Ingold-Prelogrules. The nomenclature used in the Examples is that recommended byChemical Abstracts; thus, after reaction of the acid group with anamine, certain L-proline derivatives may become2(S)-pyrrolidinecarboxamide derivatives.

In the experimental section, the "Preparations" relate to theintermediates and the "Examples" relate to the products according to theinvention.

The melting points (m.p.) indicated below are generally measured using aKoffler bench and are not corrected, so they represent instantaneousmelting points.

The spectral characteristics of the nuclear magnetic resonance (NMR)signals are given for the proton (¹ H) or for the 13 isotope of carbon(¹³ C); the chemical shift is indicated relative to thetetramethylsilane signal and is followed, in brackets, by the shape ofthe signal (s for singlet, d for doublet, t for triplet, q forquadruplet, m for multiplet, bs for broad signal) and the number ofprotons corresponding to the signal. By way of indication, the ¹ H NMRspectra were run at 300 MHz.

EXAMPLE 11-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[2-[[4-(aminoiminomethyl)phenyl]carbonylaminol]ethyl]-2(S)-pyrrolidinecarboxamide

A solution of 0.15 g (7.25.10⁻⁴ mol) of 4-(aminoiminomethyl)benzoic acidhydrochloride in 10 ml of dimethylformamide (DMF) is prepared and 0.15 g(7.98.10⁻⁴ mol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDCI) and 0.11 g (7.25.10⁻⁴ mol) of1-hydroxy-7-azabenzotriazole (HOAT) are added. The resulting mixture isstirred for 30 minutes at room temperature (about 20° C.) and a solutionof 0.4 g (7.25.10⁻⁴ mol) of1-[[3-[(2,4-dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[2-aminoethyl]-2(S)-pyrrolidine-carboxamidein 10 ml of DMF is then added dropwise. The reaction medium is stirredfor 5 hours at room temperature and then poured into iced water. 1 Nsodium hydroxide solution is then added slowly until the pH is 8, afterwhich the mixture is extracted with dichloromethane. The organic phaseis washed with water, dried over sodium sulfate and then concentratedunder reduced pressure. The crude product is purified by chromatographyon NH₂ -grafted silica gel (LICHROPREP® NH₂) using adichloromethane/methanol mixture (95/5; v/v) as the eluent to give 0.2 gof the expected product (yield=40%). The product is used directly toobtain the salt.

EXAMPLE 21-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[2-[[4-(aminoiminomethyl)phenyl]carbonylamino]ethyl]-2(S)-pyrrolidine-carboxamidedihydrochloride

0.2 g (0.287.10⁻³ mol) of the compound obtained according to Example 1is dissolved in 2 ml of 1 N hydrochloric acid solution. The solutionobtained is lyophilized. The lyophilization residue is redissolved in 2ml of distilled water and lyophilized again to give 220 mg of theexpected compound in the form of an amorphous white solid (quantitativeyield). M.p.=198° C. [α]_(D) ²⁷ =-38° (c=0.31; CH₃ OH)

EXAMPLE 31-[[3-[(2,4-Dimethylquinolin-8yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[2-[[2-[4(aminoiminomethyl)phenoxy]-1-oxoethyl]amino]ethyl]-2(S)-pyrrolidinecarboxamide

The expected product is obtained in the form of a white solid(yield=31%) by following a procedure analogous to Example 1, startingfrom 4-(aminoiminomethyl)phenoxyacetic acid hydrochloride. M.p.=156-160°C. [α]_(D) ²³ =-30° (c=0.25; CH₃ OH)

EXAMPLE 41-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[2-[[2-[4(aminoiminomethyl)phenoxy]-1-oxoethyl]amino]ethyl]-2(S)-pyrrolidinecarboxamidedihydrochloride

The expected product (practically quantitative yield) is obtained byfollowing a procedure analogous to Example 2, starting from the compoundobtained according to Example 3. M.p.=184-188° C. [α]_(D) ²⁴ =-27°(c.=0.3; CH₃ OH)

EXAMPLE 51-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[[4-(aminoiminomethyl)phenyl]carbonylamino]propyl]-2(S)-pyrrolidine-carboxamide

The expected product (yield=48%) is obtained by following a procedureanalogous to Example 1, starting from1-[[3-[(2,4-dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-aminopropyl]-2(S)-pyrrolidinecarboxamidehydrochloride and in the presence of N-methylmorpholine. M.p.=178-180°C. [α]_(D) ²⁵ =-39° (c=0.32; CH₃ OH)

EXAMPLE 61-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[[4-(aminoiminomethyl)phenyl]carbonylamino]propyl]-2(S)-pyrrolidine-carboxamidedihydrochloride

A solution of 1.3 g (1.82.10⁻³ mol) of the compound obtained accordingto Example 5 in 20 ml of ethyl acetate and 6 ml of ethanol is prepared.1.4 ml of a saturated solution of hydrogen chloride in ethyl ether areadded. The crystals formed are filtered off, washed with ethyl ether andthen redissolved in 25 ml of distilled water. The solution obtained islyophilized to give 1.25 g of the expected product in the form of anamorphous white solid (yield=87.4%). M.p=200-202° C. [α]_(D) ²⁵ =-36°(c=0.3; CH₃ OH)

EXAMPLE 71-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[[2-[4(aminoiminomethyl)phenyl]-1-oxoethyl]amino]propyl]-2(S)-pyrrolidinecarboxamide

The expected product (yield=39%) is obtained by following a procedureanalogous to Example 5, starting from 4-(aminoiminomethyl)phenylaceticacid hydrochloride. M.p.=184-188° C. [α]_(D) ²⁴ =-30° (c=0.3; CH₃ OH)

Example 81-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[-[[2-[4(aminoiminomethyl)phenyl]-1-oxoethyl]amino]propyl]-2(S)-pyrrolidinecarboxamidedihydrochloride

A solution of 120 mg (0.165.10⁻³ mol) of the compound obtained accordingto Example 7 in 5 ml of ethanol is prepared and 1 ml of a saturatedsolution of hydrogen chloride in ethyl ether is added. After the mixturehas been stirred for 30 minutes at room temperature, the reaction mediumis concentrated under reduced pressure. The residue is redissolved in 10ml of water. After filtration, the solution is lyophilized to give 130mg of the expected product in the form of a white solid (yield=98%).M.p.=186-190° C. [α]_(D) ²⁴ ==25° (c=0.30; CH₃ OH)

EXAMPLE 91-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[[2-[4(aminoiminomethyl)phenoxy]-1-oxoethyl]amino]propyl]-2(S)-pyrrolidinecarboxamide

The expected product (yield=35%) is obtained by following a procedureanalogous to Example 7, starting from 4-(aminoiminomethyl)phenoxyaceticacid hydrochloride. M.p.=124-128° C. [α]_(D) ²⁴ =-21° (c=0.32; CHCl₃)

EXAMPLE 101-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[[2-[4-(aminoiminomethyl)phenoxy]-1-oxoethyl]amino]propyl]-2(S)-pyrrolidinecarboxamidedihydrochloride

The expected product (yield=96%) is obtained by following a procedureanalogous to Example 6, starting from the compound obtained according toExample 9. M.p.=168-172° C. [α]_(D) ²⁵ ==20° (c=0.3; CH₃ OH)

PREPARATION I1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[(3-cyanophenyl)carbonylamino]propyl]-2(S)-pyrrolidinecarboxamide

By following a procedure analogous to Example 5, starting from3-cyanobenzoic acid, the expected product is obtained in the form of awhite solid after purification by chromatography on silica gel using adichloromethane/methanol mixture (98/2; v/v) as the eluent (yield=75%).M.p.=102-106° C. [α]_(D) ²⁴ =-40° (c=0.33; CH₃ OH)

PREPARATION II1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4dichlorophenyl]sulfonyl]-N-[3-[[3-[(amino)(hydroxyimino)methyl]phenyl]carbonylamino]propyl]-2(S)-pyrrolidinecarboxamide

A solution of 1.1 g (1.58.10⁻³ mol) of the compound obtained accordingto Preparation I in 30 ml of dimethyl sulfoxide is prepared and 0.55 g(7.9.10⁻³ mol) of hydroxylamine hydrochloride and then 0.8 g (7.9.10⁻³mol) of triethylamine are added. After stirring for two hours at roomtemperature, the same amounts of these two reagents are added again andstirring is continued for 4 hours. 200 ml of water are then added. Theprecipitate obtained is filtered off and redissolved in dichloromethane.The organic solution is washed with water, dried over sodium sulfate andthen concentrated under reduced pressure to give 1.13 g of the expectedproduct in the form of white crystals (yield=98%). M.p.=108-110° C.[α]_(D) ²⁴ =-30° (c=0.38; CH₃ OH)

PREPARATION III1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[[3-[(amino)(acetoxyimino)methyl]phenyl]carbonylamino]propyl]-2(S)-pyrrolidinecarboxamide

0.03 g (0.28.10⁻³ mol) of acetic anhydride is added to a solution of 0.2g (0.27.10⁻³ mol) of the compound obtained according to Preparation IIin 10 ml of anhydrous dichloromethane and the reaction mixture isstirred for 15 hours. About 50 ml of dichloromethane are added to themixture and this organic phase is washed with water and then dried oversodium sulfate. After concentration under reduced pressure, 0.20 g ofthe expected product is obtained in the form of a white solid(yield=95%). M.p.=100-104° C. [α]_(D) ²⁴ =-20° (c=0.29; CH₃ OH)

EXAMPLE 111-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[[3-(aminoiminomethyl)phenyl]carbonylamino]propyl]-2(S)-pyrrolidine-carboxamide

A solution of 0.2 g (0.26.10⁻³ mol) of the compound obtained accordingto Preparation III in 5 ml of methanol is prepared and 10 mg ofLindlar's catalyst (containing 5% of palladium) are added. The mixtureis stirred under a hydrogen atmosphere at atmospheric pressure, at roomtemperature, for 3 hours. After removal of the catalyst by filtration,the solution is concentrated under reduced pressure. The crude productobtained is purified by chromatography on NH₂ -grafted silica gel(LICHROPREP® NH₂) using a dichloromethane/methanol mixture (95/5; v/v)as the eluent to give 0.11 g of the expected product in the form of awhite solid (yield=55%). M.p.=116-120° C. [α]_(D) ²⁴ =-36° (c=0.35; CH₃OH)

EXAMPLE 121-[[3-[[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[[3-(aminoiminomethyl)phenyl]carbonylamino]propyl]-2(S)-pyrrolidine-carboxamidedihydrochloride

The expected product (yield=98%) is obtained by following a procedureanalogous to Example 8, starting from the compound obtained according toExample 11. M.p.=192-194° C. [α]_(D) ²² =-31° (c=0.3; CH₃ OH)

PREPARATION IV N-Ethyl-N-(3-aminopropyl)carbamic acid 1,1dimethylethylester

A solution of 3.42 g (0.017 mol) of N-ethyl-N-(2-cyanoethyl)carbamicacid 1,1-dimethylethyl ester in 70 ml of ethanol is prepared and 0.5 gof Raney nickel is added. The mixture is stirred under a hydrogenatmosphere at atmospheric pressure, at room temperature, for 6 hours.The catalyst is filtered off and the filtrate is then concentrated underreduced pressure. The residual oil is then purified by chromatography onNH₂ -grafted silica gel using a toluene/isopropanol mixture (95/5; v/v)as the eluent to give 1.72 g of the expected product in the form of acolorless oil (yield=50%). ¹ H NMR (300 MHz; CDCl₃) 1.09 (t, 3H); 1.28(d, 2H); 1.46 (s, 9H); 1.64 (m, 2H); 2.67 (t, 2H); 3.25 (m, 4H)

PREPARATION V1-[[3-[(2,4Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[(ethyl)(1,1-dimethylethoxycarbonyl)amino]propyl]-2(S)-pyrrolidine-carboxamide

A solution of 3.85 g (7.55.10⁻³ mol) of1-[[3-[(2,4-dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-L-prolinein 20 ml of dichloromethane is prepared and 1.59 g (8.3.10⁻³ mol) ofEDCI, 1.13 g (8.3.10⁻³ mol) of HOAT and then 1.68 g (8.3.10⁻³ mol) ofN-ethyl-N-(3-aminopropyl)carbamic acid 1,1-dimethylethyl ester areadded. The reaction mixture is stirred for 24 hours at room temperatureand then concentrated under reduced pressure. The residue is purified bychromatography on silica gel using a dichloromethane/methanol mixture(98/2; v/v) as the eluent to give 5 g of the expected product in theform of an amorphous, light yellow solid (yield=95%). M.p.=80° C.[α]_(D) ²⁵ =-34° (c=0.47; CH₃ OH)

PREPARATION VI1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-(ethylamino)propyl]-2(S)-pyrrolidinecarboxamide

3 ml of trifluoroacetic acid and 0.408 g (3.78.10⁻³ mol) of anisole areadded to a solution, cooled to 0° C. beforehand, of 2.62 g (3.78.10⁻³mol) of the compound obtained according to Preparation V in 8 ml ofdichloromethane. The reaction mixture is stirred for 1 hour at 0° C. andthen for 20 hours at room temperature. After removal of the solventunder reduced pressure, water is added to the residue and the pH of theaqueous phase is rendered basic with 1 N NaOH solution. After extractionwith ethyl acetate, the organic phase is washed with water, dried oversodium sulfate and concentrated under reduced pressure to give 2.14 g ofthe expected product in the form of a beige solid (yield 95%). M.p.=70°C. [α]_(D) ²⁵ =-44° (c=0.38; CH₃ OH)

EXAMPLE 131-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4dichlorophenyl]sulfonyl]-N-[3-[[ethyl]-[[4-(aminoiminomethyl)phenyl]carbonyl]amino]propyl]-2(S)-pyrrolidineacarboxamide

A solution of 0.2 g (0.337.10⁻³ mol) of the compound obtained accordingto Preparation VI in 10 ml of dichloromethane is prepared and 0.07 g(0.337.10⁻³ mol) of 4-(aminoiminomethy)benzoyl chloride hydrochlorideand 0.027 g (0.27.10⁻³ mol) of N-methylmorpholine are added to thesolution. The reaction mixture is stirred for 20 hours and thenconcentrated under reduced pressure. The residue is redissolved in waterand the pH of the solution is rendered slightly alkaline with 1 N NaOH.After extraction with dichloromethane, the organic phase is washed withwater, dried over sodium sulfate and concentrated under reducedpressure. The residue is purified by chromatography on NH₂ -graftedsilica using a dichloromethane/methanol mixture (95/5; v/v) as theeluent to give 0.12 g of the expected product in the form of a creamywhite solid (yield=48%). M.p.=160° C.

EXAMPLE 141-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-3-[[ethyl]-[[4-(aminoiminomethyl)phenyl]carbonyl]amino]propyl]-2(S)-pyrrolidinecarboxamide dihydrochloride

The expected product (yield=80%) is obtained by following a procedureanalogous to Example 8, starting from the compound obtained according toExample 13. M.p.=193° C. [α]_(D) ²⁵ =-27° (c=0.37; CH₃ OH)

PREPARATION VII1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[(methyl)(1,1-dimethylethoxycarbonyl)amino]propyl]-2(S)-pyrrolidinecarboxamide

The product (yield=73%) is obtained by following a procedure analogousto Preparation V, starting from N-methyl-N-(3-aminopropyl)carbamic acid1,1-dimethylethyl ester. M.p.=80° C. [α]_(D) ²⁵ =-40° (c=0.42; CH₃ OH)

PREPARATION VIII1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-(methylamino)propyl]-2(S)-pyrrolidinecarboxamide

The expected product (yield=92%) is obtained by following a procedureanalogous to Preparation VI, starting from the compound obtainedaccording to Preparation VII. M.p.=85° C. [α]_(D) ²⁵ =-37° (c=0.39; CH₃OH)

EXAMPLE 151-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[[methyl]-[[4-(aminoiminomethyl)phenyl]carbonyl]amino]propyl]-2(S)-pyrrolidinecarboxamide

The expected product (yield=51%) is obtained by following a procedureanalogous to Example 13, starting from the compound obtained accordingto Preparation VIII. M.p.=158° C. [α]_(D) ²⁵ =-29° (c=0.55; CH₃ OH)

EXAMPLE 161-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[[methyl]-[[4(aminoiminomethyl)phenyl]carbonyl]amino]propyl]-2(S)-pyrrolidinecarboxamidedihydrochloride

The expected product (yield=76%) is obtained by following a procedureanalogous to Example 8, starting from the compound obtained according toExample 15. M.p.=196° C. [α]_(D) ²⁵ =-29° (c=0.36; CH₃ OH)

PREPARATION IX1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[(4-cyanophenyl)carbonylamino]propyl]-2(S)-pyrrolidinecarboxamide

By following a procedure analogous to Example 5, starting from4-cyanobenzoic acid and1-[[3-[(2-methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-aminopropyl]-2(S)-pyrrolidinecarboxamidehydrochloride, the expected product (yield=75%) is obtained afterpurification by chromatography on silica gel using adichloromethane/methanol mixture (98/2; v/v) as the eluent. M.p.=78-80°C. [α]_(D) ²⁴ =-39° (c=0.3; CH₃ OH)

PREPARATION X1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[[4-[(amino)(hydroxyimino)methyl]phenyl]carbonylamino]propyl]-2(S)-pyrrolidinecarboxamide

The expected product (yield=70%) is obtained by following a procedureanalogous to Preparation II, starting from the compound obtainedaccording to Preparation IX. M.p.=120-124° C. [α]_(D) ²⁴ =-35° (c=0.3;CH₃ OH)

PREPARATION XI1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[[4-[(amino)(acetoxyimino)methyl]phenyl]carbonylamino]propyl]-2(S)-pyrrolidinecarboxamide

The expected product (yield=72%) is obtained by following a procedureanalogous to Preparation III, starting from the compound obtainedaccording to Preparation X.

M.p.=122-126° C.

[α]_(D) ²⁴ =-36° (c=0.27; CH₃ OH)

EXAMPLE 171-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[[4-(aminoiminomethyl)phenyl]carbonylamino]propyl]-2(S)-pyrrolidinecarboxamide

The expected product (yield=76%) is obtained by following a procedureanalogous to Example 11, starting from the compound obtained accordingto Preparation XI.

M.p.=118-120° C.

[α]_(D) ²⁴ =-38° (c=0.35; CH₃ OH)

EXAMPLE 181-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[[4-(aminoiminomethyl)phenyl]carbonylamino]propyl]-2(S)-pyrrolidinecarboxamidedihydrochloride

The expected product (yield=97%) is obtained by following a procedureanalogous to Example 8, starting from the compound obtained according toExample 17.

M.p.=186-188° C.

[α]_(D) ²³ =-37° (c=0.3; CH₃ OH)

EXAMPLE 191-[[3-[(2,4-Dimethylquinolin-8-yloxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[4-[[4-(aminoiminomethyl)phenyl]carbonylamino]butyl]-2(S)-pyrrolidinecarboxamidedihydrochloride

A solution of 0.34 g (1.69.10⁻³ mol) of 4-(aminoiminomethyl)benzoic acidhydrochloride in 5 ml of dimethylformamide (DMF) is prepared and 0.46 g(1.69.10⁻³ mol) of EDCI and 0.32 g (1.69.10⁻³ mol) of HOAT are added.The mixture is stirred for 30 minutes at room temperature. The solutionobtained is then added dropwise to a solution of 1 g (1.53.10⁻³ mol) of1-[[3-[(2,4-dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[4-aminobutyl]-2(S)-pyrrolidinecarboxamide(in the form of the dihydrochloride) in 5 ml of DMF and 0.46 g (4.6.10⁻³mol) of triethylamine. The reaction mixture is stirred for 4 hours atroom temperature and then poured into iced water. 1 N NaOH solution isadded slowly to bring the pH to 8 and the mixture is extracted severaltimes with dichloromethane. The combined organic phases are washed withwater, dried over sodium sulfate and then concentrated under reducedpressure. The crude product is purified by chromatography a first timeon NH₂ -grafted silica gel using a dichloromethane/methanol mixture(98/2; v/v) as the eluent, and a second time on C18-grafted silica gel(type RP18) using a mixture of dichloromethane and 0.2 N HCl gas inmethanol (98/2; v/v) as the eluent. After removal of the solvents underreduced pressure, the product is dissolved in 5 ml of distilled waterand the solution is lyophilized to give 150 mg of the expected productin the form of a pale yellow solid (yield=13%).

M.p.=196-200° C.

[α]_(D) ²⁶ =-20° (c 0.285; CH₃ OH)

PREPARATION XII1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[5-[(1,1-dimethylethoxycarbonyl)amino]pentyl]-2(S)-pyrrolidinecarboxamide

The expected product (yield=43%) is obtained by following a procedureanalogous to Preparation V, starting from (5-aminopentyl)carbamic acid1,1-dimethylethyl ester.

M.p.=78-82° C.

PREPARATION XIII

[1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-(5-aminopentyl)-2(S)-pyrrolidinecarboxamidedihydrochloride

2.9 g (4.2.10⁻³ mol) of the compound obtained according to PreparationXII are added to 25 ml of 1 N hydrochloric acid solution and the mixtureis stirred at 50° C. for 3 hours. The reaction medium is then cooled to15° C. and washed with ethyl acetate. The aqueous phase is concentratedunder reduced pressure and then taken up with 50 ml of distilled water.The solution is filtered and then lyophilized to give the expectedproduct in the form of a white solid (yield=90%).

M.p.=162-166° C.

[α]_(D) ²⁴ =-29° (c=0.31; CH₃ OH)

EXAMPLE 20 1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]2,4-dichlorophenyl]sulfonyl]-N-[5-[[4-(aminoiminomethyl)phenyl]carbonylamino]pentyl]-2(S)-pyrrolidinecarboxamide

The expected product (yield=30%) is obtained by following a procedureanalogous to Example 1, starting from the compound obtained according toPreparation XIII.

M.p.=150-152° C.

[α]_(D) ²⁴ =-14° (c=0.32; CH₃ OH)

EXAMPLE 211-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[5-[[4-(aminoiminomethyl)phenyl]carbonylamino]pentyl]-2(S)-pyrrolidinecarboxamidedihydrochloride

The expected product (yield=97%) is obtained by following a procedureanalogous to Example 8, starting from the compound obtained according toExample 20.

M.p.=182-185° C.

[α]_(D) ²⁵ =-15° (c=0.31; CH₃ OH)

PREPARATION XIVN-(Methyl)-N-[3-[(4-cyanophenyl)carbonylamino]propyl]carbamic acid1,1-dimethylethyl ester

A solution of 1.23 g (6.53.10⁻³ mol) ofN-methyl-N-[3-aminopropyl]-carbamic acid 1,1-dimethylethyl ester in 10ml of dichloromethane and 5 ml of pyridine is prepared and 1.08 g(6.53.10⁻³ mol) of 4-cyanobenzoyl chloride are added. After stirring for20 hours at room temperature, dichloromethane is added and this organicphase is washed with water, then with 1 N hydrochloric acid solution andthen with water again. After drying over magnesium sulfate, the organicphase is concentrated under reduced pressure. The residue obtained ispurified by chromatography on silica gel using a toluene/ethyl acetatemixture (8/2; v/v) as the eluent to give 1 g of the expected product inthe form of a creamy white solid (yield=48%).

M.p.<50° C.

PREPARATION XV 4-Cyano-N-[3-(methylamino)propyl]benzamide

The expected product is obtained in the form of a light yellow oil(yield=89%) by following a procedure analogous to Preparation VI,starting from the compound obtained according to Preparation XIV.

¹ H NMR (DMSO)

1.70 (q, 2H); 2.34 (s, 3H); 2.61 (t, 3H); 3.3 (m, 3H); 7.97 (s, 4H);8.83 (bs, 1H)

PREPARATION XVI1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[methyl]-N-[3-[(4-cyanophenyl)carbonylamino]propyl]-2(S)-pyrrolidinecarboxamide

The expected product (yield=40%) is obtained by following a procedureanalogous to Preparation V, starting from the compound obtainedaccording to Preparation XV.

M.p.=100° C.

[α]_(D) ¹⁹ =-30° (c=0.32; CH₃ OH)

PREPARATION XVII 1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl-2,4-dichlorophenyl]sulfonyl]-N-[methyl]-N-[3-[[4-[amino(hydroxyimino)methyl]phenyl]carbonylamino]-propyl]-2(S)-pyrrolidinecarboxamide

The expected product (yield=95%) is obtained by following a procedureanalogous to Preparation II, starting from the compound obtained inPreparation XVI.

M.p.=65-70° C.

[α]_(D) ¹⁸ =+18° (c =0.25; CH₃ OH)

PREPARATION XVIII1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[methyl]-N-[3-[[4-[amino(acetoxyimino)methyl]phenyl]carbonylamino]-propyl]-2(S)-pyrrolidinecarboxamide

The expected product (yield=87%) is obtained by following a procedureanalogous to Preparation III, starting from the compound obtained inPreparation XVII.

M.p.=70° C.

[α]_(D) ¹⁹ =-4.3° (c=0.32; CH₃ OH)

EXAMPLE 221-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[methyl]-N-[3-[[4-(aminoiminomethyl)phenyl]carbonylamino]propyl]-2(S)-pyrrolidinecarboxamide

The expected product (yield=73%) is obtained by following a procedureanalogous to Example 11, starting from the compound obtained inPreparation XVIII.

M.p.=133° C.

[α]_(D) ¹⁹ =-40° (c=0.33; CH₃ OH)

EXAMPLE 231-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[methyl]-N-[3-[[4-(aminoiminomethyl)phenyl]carbonylamino]propyl]-2(S)-pyrrolidinecarboxamidedihydrochloride

A solution of 0.15 g (0.20.10⁻³ mol) of the compound obtained accordingto Example 22 in 5 ml of anhydrous methanol is prepared and 1 ml ofethyl ether saturated with hydrogen chloride is added. The mixture isstirred for 10 minutes and 20 ml of ethyl ether are then added. Theprecipitate obtained is filtered off, rinsed with ether and redissolvedin 5 ml of distilled water. After lyophilization of the solution, 0.15 gof the expected product is obtained in the form of a yellowish whitesolid (yield=91%).

M.p.=211° C.

[α]_(D) ⁹ =-8° (c=0.32; CH₃ OH)

PREPARATION XIX1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[methyl]-N-[3-[(methyl)(1,1-dimethylethoxycarbonyl)amino]propyl]-2(S)-pyrrolidinecarboxamide

The expected product (yield=78%) is obtained by following a procedureanalogous to Preparation VII, starting fromN-methyl-N-[3-(methylamino)propyl]carbamic acid 1,1-dimethylethyl ester.

M.p.=50° C.

[α]_(D) ^(<) =-17° (c=0.38; CH₃ OH)

PREPARATION XX1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[methyl]-N-[3-(methylamino)propyl]-2(S)-pyrrolidinecarboxamide

The expected product (yield=99%) is obtained by following a procedureanalogous to Preparation VIII, starting from the compound obtainedaccording to Preparation XIX.

M.p.=150° C.

[α]_(D) ²¹ =-26° (c=0.33; CH₃ OH)

PREPARATION XXI1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[methyl]-N[3-[(methyl)[(4-cyanophenyl)carbonyl]amino]propyl]-2(S)-pyrrolidinecarboxamide

The expected product (yield=90%) is obtained by following a procedureanalogous to Preparation I, starting from the compound obtainedaccording to Preparation XX and 4-cyanobenzoic acid.

M.p.=60° C.

[α]_(D) ²¹ =+6° (c=0.72; CH₃ OH)

PREPARATION XXII1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[methyl]-N-[3-[(methyl)[[4-[amino(hydroxyimino)methyl]phenyl]carbonyl]-amino]propyl]-2(S)-pyrrolidinecarboxamide

The expected product is obtained in the form of an oily product(yield=77%) by following a procedure analogous to Preparation II,starting from the compound obtained in Preparation XXI.

n_(D) ²³ =1.571

[α]_(D) ²¹ =-18° (c=0.55; CH₃ OH)

PREPARATION XXIII1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[methyl]-N-[3-[(methyl)[[4-(amino(acetoxyimino)methyl]phenyl]carbonyl]-amino]propyl]-2(S)-pyrrolidinecarboxamide

The expected product (yield=60%) is obtained by following a procedureanalogous to Preparation III, starting from the compound obtained inPreparation XXIII.

M.p.=70° C.

[α]_(D) ²¹ =-12° (c=0.45; CH₃ OH)

EXAMPLE 241-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[methyl]-N-[3-[(methyl)[[4-(aminoiminomethyl)phenyl]carbonyl]amino]-propyl]-2(S)-pyrrolidinecarboxamide

The expected product (yield=72%) is obtained by following a procedureanalogous to Example 11, starting from the compound obtained inPreparation XXIII.

M.p.=170° C.

[α]_(D) ²¹ =-16.2° (c=0.69; CH₃ OH)

EXAMPLE 251-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[methyl]-N-[3-[(methyl)[[4-(aminoiminomethyl)phenyl]carbonyl]amino]-propyl]-2(S)pyrrolidinecarboxamide dihydrochloride

The expected product (yield=86%) is obtained by following a procedureanalogous to Example 8, starting from the compound obtained in Example22.

M.p.=175° C.

[α]_(D) ² =-2.4° (c=0.38; CH₃ OH)

PREPARATION XXIV1-[[3-[(2,4-Dimethylquinolin-8-yloxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[(5-cyanopyridin-2-yl)carbonylamino]propyl]-2(S)-pyrrolidinecarboxamide

A suspension of 1.90 g (10.3.10⁻³ mol) of 5-cyanopicolinic acidhydrochloride in 50 ml of dichloromethane is prepared and 1.10 ml(34.10⁻³ mol) of N-methylmorpholine are added. After stirring for 30min, 1.68 g (12.3.10⁻³ mol) of HOAT and then 2.37 g (12.3.10⁻³ mol) ofEDCI are added. The mixture is stirred for 1 hour at room temperatureand 6.65 g (10.3.10⁻³ mol) of1-[[3-[(2,4-dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-aminopropyl]-2(S)-pyrrolidinecarboxamidehydrochloride and 2.55 ml (72.10⁻³ mol) of N-methylmorpholine dissolvedin 30 ml of dichloromethane are then added dropwise. After stirringovernight at room temperature, the reaction mixture is poured into 100ml of water and then extracted twice with dichloromethane. The combinedorganic phases are washed with water, dried over magnesium sulfate andconcentrated under reduced pressure. The crude product obtained (3.16 g)is purified by chromatography on silica gel using ethyl acetate as theeluent to give 2.18 g of the expected product in the form of lightyellow crystals (yield=30.4%).

M.p.=91-93° C.

[α]_(D) ²⁰ =-39° (c=0.99; CH₃ OH)

PREPARATION XXV1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[[5-[(amino)(hydroxyimino)methyl]pyridin-2-yl]carbonylamino]propyl]-2(S)-pyrrolidinecarboxamide

The expected product is obtained in the form of pale yellow crystals(yield=72%) by following a procedure analogous to Preparation II,starting from the compound obtained according to Preparation XXIV.

M.p.=134-136° C.

[α]_(D) ²¹ =-32° (c=1.00; CH₃ OH)

PREPARATION XXVI1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[[5-[(amino)(acetoxyimino)methyl]pyridin-2-yl]carbonylamino]propyl]-2(S)-pyrrolidinecarboxamide

The expected product is obtained in the form of creamy white crystals(yield=92%) by following a procedure analogous to Preparation III,starting from the compound obtained according to Preparation XXV.

M.p.=116-118° C.

[α]_(D) ²² =-13° (c=1.05; CH₃ OH)

EXAMPLE 261-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[[5-(aminoiminomethyl)pyridin-2-yl]carbonylamino]propyl]-2(S)-pyrrolidinecarboxamide

The expected product is obtained in the form of white crystals(yield=65%) by following a procedure analogous to Example 11, startingfrom the compound obtained according to Preparation XXVI.

M.p.=145-147° C.

[α]_(D) ²² =-36° (c=1.03; CH₃ OH)

EXAMPLE 271-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[[5-(aminoiminomethyl)pyridin-2-yl]carbonylamino]propyl]-2(S)-pyrrolidinecarboxamidedi(methanesulfonate)

A solution of 0.64 g (0.9.10⁻³ mol) of the compound obtained accordingto Example 26 in 12.5 ml of methanol is prepared and 86.3 mg ofmethanesulfonic acid are added. The mixture is stirred for one hour atroom temperature and then poured into 700 ml of ethyl ether, withstirring. The precipitate obtained is filtered off, washed with etherand then redissolved in 60 ml of water. The solution obtained isfiltered and lyophilized to give 0.675 g of the expected product in theform of white flakes (yield=92%).

M.p.=160° C. (decomposition)

[α]_(D) ²¹ =-21° (c=1.03; CH₃ OH)

PREPARATION XXVII3-[[1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-pyrrolidin-2-yl]carbonylamino]propionicacid methyl ester

A mixture of 6.85 g (13.4.10⁻³ mol) ofN-[[3-[(2,4-dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-L-proline,2.01 g (14.7.10⁻³ mol) of HOAT and 2.83 g (14.7.10⁻³ mol) of EDCI in 50ml of dimethylformamide is prepared. After stirring for 15 min at roomtemperature, this mixture is added dropwise to a solution of 2.06 g ofmethyl 4-aminobutyrate (in the form of the hydrochloride) in 35 ml ofdimethylformamide and 1.48 ml (13.4.10⁻³ mol) of N-methylmorpholine. Thereaction mixture is stirred for 20 hours at room temperature and 500 mlof dichloromethane are then added, followed by 300 ml of water. Afterdecantation, the organic phase is washed twice with water again, driedover sodium sulfate and then concentrated under reduced pressure. Thecrude product obtained is purified by chromatography on silica gel usinga cyclohexane/ethyl acetate mixture (3/7; v/v) as the eluent to give 5.3g of the expected product in the form of yellow crystals (yield=64.5%).

M.p.=64-67° C.

[α]_(D) ²⁴ =-40.4° (c=1.10; CH₂ Cl₂)

PREPARATION XXVIII3-[[1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-pyrrolidin-2-yl]carbonylamino]propionicacid hydrochloride

A mixture of 5.07 g of the compound obtained according to PreparationXXII with 9.1 ml of 1 N aqueous sodium hydroxide solution is heated at90-100° C. for 1 hour. After cooling, 30 ml of water are added and theaqueous phase is extracted twice with 50 ml of ethyl acetate and thenacidified to pH 1 with 1 N hydrochloric acid solution. The insolubleproduct is redissolved in dichloromethane and the organic phase iswashed with a small amount of water, dried over sodium sulfate andconcentrated under reduced pressure to give 2.8 g of the expectedproduct in the form of white crystals (yield=53%).

M.p.=146-148° C.

[α]_(D) ²⁴ =-21.2° (c=1.00; CH₃ OH)

EXAMPLE 281-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[[4-(aminoiminomethyl)phenyl]methylaminocarbonyl]propyl]-2(S)-pyrrolidinecarboxamide

A solution of 2 g (1.58.10⁻³ mol) of the acid obtained according toPreparation XXVIII in 20 ml of dimethylformamide is prepared and 0.364 g(1.89.10⁻³ mol) of EDCI and 0.723 g (1.89.10⁻³ mol) of HATU[O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate] are added. After stirring for 30 min, 0.52 ml(4.7.10⁻³ mol) of N-methylmorpholine and then 0.352 g (1.58.10⁻³ mol) of4-(aminoiminomethyl)phenylmethanamine dihydrochloride are added. Thereaction mixture is stirred for 16 hours at room temperature and 150 mlof ethyl ether are then added. The precipitate formed is filtered off,washed with water, then with 10 ml of 1 N sodium hydroxide solution andthen with water again and dried in a desiccator. The resulting crudeproduct is purified by chromatography on NH₂ -grafted silica gel using adichloromethane/ethanol mixture (95/5; v/v) as the eluent to give 0.21 gof the expected product in the form of white crystals (yield=18%).

M.p.=112-114° C.

[α]_(D) ²³ =-24° (c=0.64; CHCl₃)

EXAMPLE 291-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[[4-(aminoiminomethyl)phenyl]methylaminocarbonyl]propyl]-2(S)-pyrrolidinecarboxamidehydrochloride

A solution of 0.169 g (0.23.10⁻³ mol) of the compound obtained accordingto Example 28 in 8 ml of dichloromethane is prepared and 0.23 ml of asolution containing 1 mol/l of hydrogen chloride in ethyl ether isadded. After stirring for one hour at room temperature, the mixture isconcentrated under reduced pressure. The residue is taken up with ethylether and filtered off. The solid obtained is washed with ether and thenredissolved in 20 ml of water. The solution obtained is filtered andlyophilized to give 0.16 g of the expected product in the form of whitecrystals (yield=90%).

M.p.=178-180° C.

[α]_(D) ²⁷ =-3.5° (c=0.96; C₂ H₅ OH)

EXAMPLE 301-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[[4-(aminoiminomethyl)phenyl]aminocarbonyl]propyl]-2(S)-pyrrolidinecarboxamide

The expected product is obtained in the form of white crystals(yield=10%) by following a procedure analogous to Example 28, startingfrom the acid obtained according to Preparation XXVIII and4-(aminoiminomethyl)aniline.

M.p.=140-141° C.

EXAMPLE 311-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[[4-(aminoiminomethyl)phenyl]aminocarbonyl]propyl]-2(S)-pyrrolidinecarboxamidehydrochloride

The expected product is obtained in the form of white crystals(yield=90%) by following a procedure analogous to Example 29, startingfrom the compound obtained according to Example 30.

M.p.=192-193° C.

PREPARATION XXIX 4-[(2-Methoxyphenyl)imino]-1,1,1-trifluoro-2-pentanone

A mixture of 28.4 g (0.23 mol) of 2-methoxyaniline and 43.2 g (0.28 mol)of 1,1,1-trifluoro-2,4-pentanedione is prepared and heated at 100-105°C. for 1 h, with stirring. After cooling, the reaction mixture isredissolved in ethyl ether and the solution obtained is dried oversodium sulfate and then concentrated under reduced pressure to give 59.1g of the expected product in the form of a beige solid (yield=99%).

M.p.=40° C.

PREPARATION XXX 8-Methoxy-2-methyl-4-(trifluoromethyl)quinoline

10 g (38.10⁻³ mol) of the compound obtained according to PreparationXXIX are mixed with 50 g of polyphosphoric acid and the mixture isheated at 165° C. for 3 hours, with stirring. After cooling, thereaction medium is poured into iced water. The mixture obtained isextracted with ethyl ether and the organic phase is washed with sodiumbicarbonate solution, with dilute hydrochloric acid solution and thenwith water. After drying of the organic phase and concentration underreduced pressure, 5.2 g of the expected product are obtained in the formof a cream-colored solid (yield=56%).

M.p.=112-113° C.

PREPARATION XXXI 8-Hydroxy-2-methyl-4-(trifluoromethyl)quinoline

A solution of 6.15 g (25.5. 10⁻³ mol) of the compound obtained accordingto Preparation XXX in 200 ml of dichloromethane is cooled to -60° C. and130 ml of a 1 M solution of boron tribromide in dichloromethane areadded dropwise, with stirring. The reaction medium is allowed to returnto room temperature and stirred for 12 hours. The mixture is cooled to-60° C. and 140 ml of methanol are added slowly. It is then allowed toreturn to room temperature and stirred for 2 hours. The mixture is thenconcentrated under reduced pressure and the residue is taken up withdichloromethane. The organic phase is washed with sodium bicarbonatesolution and then with water, and then dried over sodium sulfate andconcentrated under reduced pressure to give 5.60 g of the expectedproduct in the form of a yellow solid (yield=96%).

M.p.=60-61° C.

PREPARATION XXXIIN-[[3-[[2-Methyl-4-(trifluoromethyl)quinolin-8-yl]oxymethyl]-2,4-dichlorophenyl]sulfonyl]-L-prolinemethyl ester

A solution of 1.08 g (4.8.10⁻³ mol) of the compound obtained accordingto Preparation XXXI in 20 ml of dimethylformamide is prepared and 0.156g (5.2.10⁻³ mol) of sodium hydride as an 80% suspension in oil is added.After stirring for one hour at room temperature, 2.05 g (4.8.10⁻³ mol)of N-[(3-bromomethyl-2,4-dichlorophenyl)sulfonyl]-L-proline methyl esterdissolved in 25 ml of dimethylformamide are added. The reaction mixtureis stirred for 24 hours at room temperature and 250 ml of water are thenadded slowly. The mixture is extracted several times with ethyl etherand the combined organic phases are washed with water, dried and thenconcentrated under reduced pressure. The crude product obtained ispurified by chromatography on silica gel using a cyclohexane/ethylacetate mixture (70/30; v/v) as the eluent to give 1.23 g of theexpected product in the form of a white solid (yield=45%).

M.p.=164-165° C.

[α]_(D) ²¹ =-16° (c=1.00; CH₂ Cl₂)

PREPARATION XXXIIIN-[[3-[[2-Methyl-4-(trifluoromethyl)quinolin-8-yl]oxymethyl]-2,4-dichlorophenyl]sulfonyl]-L-proline

A solution of 1.08 g (1.9.10⁻³ mol) of the ester obtained according toPreparation XXXII in 10 ml of methanol and 10 ml of 1 N aqueous sodiumhydroxide solution is prepared, the mixture is heated at 90-100° C. for2 hours, with stirring, and the reaction medium is then concentratedunder reduced pressure. The residue is taken up with water, ethyl etheris added and the mixture is acidified to pH 2.5 with dilute hydrochloricacid solution. After decantation and extraction of the aqueous phasewith ethyl ether, the combined organic phases are washed with water,dried and then concentrated under reduced pressure. After purificationby chromatography on silica gel using an ethyl acetate/methanol mixture(90/10; v/v) as the eluent, 0.95 g of the expected product is obtainedin the form of a cream-colored powder (yield=90%).

M.p.=215° C.

[α]_(D) ²⁵ =-2.3° (c=0.78; DMSO)

PREPARATION XXXIV [3-[(4-Cyanobenzoyl)amino]propyl]carbamic acid1,1-dimethylethyl ester

A solution of 10 g (57.10⁻³ mol) of (3-aminopropyl)carbamic acid1,1-dimethylethyl ester (or N-Boc-1,3-propanediamine) in 75 ml ofdichloromethane is prepared and 15.9 ml (114.10⁻³ mol) of triethylamineare added. The mixture is cooled with an ice bath and 10.38 g (60.10⁻³mol) of 4-cyanobenzoyl chloride are added gradually. The reaction mediumis allowed to return to room temperature, stirred for 10 hours and thenpoured into 150 ml of water. The mixture is extracted withdichloromethane and the organic phase obtained is washed with 1 Nhydrochloric acid solution and then with water and finally dried oversodium sulfate and concentrated under reduced pressure to give 16.4 g ofthe expected product in the form of ochre crystals (yield=94%).

¹ H NMR (DMSO) 1.37 (s, 9H); 1.63 (m, 2H); 2.97 (m, 2H); 3.26 (m, 2H);6.84 (t, lH); 7.97 (s, 4H); 8.70 (t, 1)

PREPARATION XXXV N-(3-Aminopropyl)-4-cyanobenzamide hydrochloride

16.4 g (54.10⁻³ mol) of the compound obtained according to PreparationIII are dissolved in 150 ml of ethyl acetate, and 104 ml of a solutioncontaining 2.6 mol/l of hydrogen chloride in ethyl acetate are thenadded. The mixture is stirred at room temperature for 24 hours and thenconcentrated under reduced pressure. The resulting crude product iswashed with ethyl ether and dried under vacuum at 40° C. to give 12.15 gof the expected product in the form of an off-white solid (yield=94%).

M.p.=176-180° C.

PREPARATION XXXVI1-[[3-[[2-Methyl-4-(trifluoromethyl)quinolin-8-yl]oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[(4-cyanophenyl)carboxy]amino]propyl]-2(S)-pyrrolidinecarboxamide

The expected product is obtained in the form of white crystals(yield=53%) by following a procedure analogous to Preparation V,starting from the compounds obtained according to Preparations XXXII andXXXV and in the presence of N-methylmorpholine.

M.p.=92-94° C.

[α]_(D) ²⁴ =-30° (c=1.01; CHCl₃)

PREPARATION XXXVII1-[[3-[[2-Methyl-4-(trifluoromethyl)quinolin-8-yl]oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[[4-[(amino)(hydroxyimino)methyl]phenyl]carbonylamino]propyl]-2(S)-pyrrolidinecarboxamide

The expected product is obtained in the form of yellow crystals(yield=16%) by following a procedure analogous to Preparation II,starting from the compound obtained according to Preparation XXXVI.

M.p.=192-194° C.

[α]_(D) ²² =-11° (c=1.00; DMSO)

PREPARATION XXXVIII1-[[3-[[2-Methyl-4-(trifluoromethyl)quinolin-8-yl]oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[[4-[(amino)(acetoxyimino)methyl]phenyl]carbonylamino]propyl]-2(S)-pyrrolidinecarboxamide

The expected product is obtained in the form of white crystals(yield=96%) by following a procedure analogous to Preparation III,starting from the compounds obtained according to Preparation XXXVII.

M.p.=170-172° C.

[α]_(D) ²⁴ =-13° (c=0.49; DMSO)

EXAMPLE 321-[[3-[[2-Methyl-4-(trifluoromethyl)quinolin-8-yl]oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[[4-(aminoiminomethyl)phenyl]carbonylamino]propyl]-2(S)-pyrrolidinecarboxamide

The expected product is obtained in the form of a pale yellow solid(yield=70%) by following a procedure analogous to Example 11, startingfrom the compounds obtained according to Preparation XXXVIII.

M.p.=142-144° C.

[α]_(D) ²⁴ =-35 (c=0.95; CH₃ OH)

EXAMPLE 331-[[3-[[2-Methyl-4-(trifluoromethyl)quinolin-8-yl]oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[[4-(aminoiminomethyl)phenyl]carbonylamino]propyl]-2(S)-pyrrolidinecarboxamidemethanesulfonate

The expected product is obtained, after lyophilization, in the form ofpale yellow flakes (yield=97%) by following a procedure analogous toExample 27, starting from the compound obtained according to Example 32.

M.p.=150-154° C.

[α]_(D) ²¹ =-33.5° (c=0.98; CH₃ OH)

PREPARATION XXXIX 2,6-Dimethyl-3-(chlorosulfonyl)benzoic acid

4 ml of chlorosulfonic acid are added slowly to 1 g (0.067 mol) of2,6-dimethylbenzoic acid and the reaction mixture is stirred for 1 hourat 55° C. After cooling, the mixture is poured into 100 ml of icedwater. The precipitate formed is filtered off, washed with cold waterand then dried in a desiccator under vacuum to give 1.22 g of theexpected product in the form of a white solid (yield=73%).

M.p.=146° C.

PREPARATION XL2,6-Dimethyl-3-[[2(S)-(methoxycarbonyl)pyrrolidin-1-yl]sulfonyl]benzoicacid

The expected product is obtained in the form of a cream-colored solid(yield=32%) by following a procedure analogous to Preparation XIV,starting from the acid chloride obtained according to Preparation XXXIXand L-proline methyl ester.

M.p.=110° C.

[α]_(D) ²⁹ =-30.5° (c 0.60; CH₃ OH)

PREPARATION XLIN-[(2,4-Dimethyl-3-(chlorocarbonyl)phenyl)sulfonyl]-L-proline methylester

A suspension of 0.77 g (2.26.10⁻³ mol) of the acid obtained according toPreparation XL in 25 ml of toluene is prepared and 0.30 g (2.5.10⁻³ mol)of thionyl chloride is added. The reaction mixture is refluxed for 4hours, with stirring, and then concentrated under reduced pressure. Theoily residue crystallizes on cooling to give 0.80 g of the expectedproduct in the form of a beige solid (yield=98%).

M.p.=92° C.

[α]_(D) ²⁶ =-13° (c=0.33; CHCl₃)

PREPARATION XLIIN-[(2,4-Dimethyl-3-(hydroxymethyl)phenyl)sulfonyl]-L-proline methylester

A solution of 0.83 g (2.31.10⁻³ mol) of the acid chloride obtainedaccording to Preparation XLI in 30 ml of diglyme is prepared and 0.1 gof sodium borohydride is added in portions at 80° C. The reactionmixture is stirred for 30 minutes at 80° C. and then cooled. Water isadded and the mixture is extracted 3 times with ethyl acetate. Thecombined organic phases are washed with water, dried over magnesiumsulfate and then concentrated under reduced pressure. The crude productis purified by chromatography on silica gel using adichloromethane/ethyl acetate mixture (9/1; v/v) as the eluent to give500 mg of the expected product in the form of an oil (yield=69%).

[α]_(D) ²⁶ =-28.5° (c=0.66; CH₃ OH)

PREPARATION XLIIIN-1-[[2,4-Dimethyl-3-(methylsulfonylmethyl)phenyl]sulfonyl]-L-prolinemethyl ester

A solution of 0.46 g (1.4.10⁻³ mol) of the alcohol obtained according toPreparation XLII in 7 ml of dichloromethane is cooled to 0° C. and 0.356g (3.5.10⁻³ mol) of triethylamine and then 0.37 g (3.2.10⁻³ mol) ofmethanesulfonyl chloride are added. The mixture is stirred for 3 hoursat room temperature and subsequently washed with sodium bicarbonatesolution and then with water. The organic phase is dried and thenconcentrated under reduced pressure to give 0.57 g of an oil containingpredominantly the expected product and the correspondingchloromethylated derivative. This oil is used directly for the nextstep.

PREPARATION XLIVN-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dimethylphenyl]sulfonyl]-L-prolinemethyl ester

45 mg (1.5.10⁻³ mol) of sodium hydride (as an 80% suspension in oil) areadded to a solution of 0.23 g (1.3.10⁻³ mol) of2,4-dimethyl-8-hydroxyquinoline in 5 ml of dimethylformamide. Afterstirring for 30 minutes at room temperature, a solution of 550 mg of thecompound obtained according to Preparation XLIII in 3 ml ofdimethylformamide is added. After stirring for 3 hours at roomtemperature, the reaction mixture is poured into 100 ml of iced waterand extracted twice with ethyl acetate. The combined organic phases arewashed with water, dried over magnesium sulfate and concentrated underreduced pressure. The residue is purified by chromatography on silicagel using a dichloromethane/ethyl acetate mixture (80/20; v/v) as theeluent to give 367 mg of the expected product in the form of anamorphous solid (yield=56%).

M.p.=50° C.

[α]_(D) ²⁶ =-15° (c=0.39; CH₃ OH)

PREPARATION XLVN-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dimethylphenyl]sulfonyl]-L-proline

The expected product is obtained in the form of a white solid(yield=88%) by following a procedure analogous to Preparation XXXIII,starting from the compound obtained according to Preparation XLIV.

M.p.=136° C.

[α]_(D) ²⁶ =-67° (c=0.57; CH₃ OH)

PREPARATION XLVI1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dimethylphenyl]sulfonyl]-N-[3-[(4-cyanophenyl)carbonylamino]propyl]-2(S)-pyrrolidinecarboxamide

The expected product is obtained in the form of white crystals(yield=78%) by following a procedure analogous to Preparation V,starting from the compounds obtained according to Preparations XLV andXXXV.

M.p.=68° C.

[α]_(D) ²³ =-28° (c 0.33; CH₃ OH)

PREPARATION XLVII1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dimethylphenyl]sulfonyl]-N-[3-[[4-[(amino)(hydroxyimino)methyl]phenyl]carbonylamino]propyl]-2(S)-pyrrolidinecarboxamide

The expected product is obtained in the form of a white solid(yield=93%) by following a procedure analogous to Preparation II,starting from the compound obtained according to Preparation XLVI.

M.p.=130° C.

[α]_(D) ²³ =-23° (c 0.40; CH₃ OH)

PREPARATION XLVIII1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dimethylphenyl]sulfonyl]-N-[3-[[4-[(amino)(acetoxyimino)methyl]phenyl]carbonylamino]propyl]-2(S)-pyrrolidinecarboxamide

The expected product is obtained in the form of white crystals(yield=93%) by following a procedure analogous to Preparation III,starting from the compound obtained according to Preparation XLVII.

M.p.=60° C.

[α]_(D) ²³ =-24° (c=0.39; CH₃ OH)

EXAMPLE 341-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dimethylphenyl]sulfonyl]-N-[3-[[4(aminoiminomethyl)phenyl]carbonylamino]propyl]-2(S)-pyrrolidinecarboxamide

The expected product is obtained in the form of a white solid(yield=79%) by following a procedure analogous to Example 11, startingfrom the compound obtained according to Preparation XLVIII.

M.p.=150° C.

[α]_(D) ²³ =-35° (c=0.39; CH₃ OH)

EXAMPLE 351-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dimethylphenyl]sulfonyl]-N-[3-[[4(aminoiminomethyl)phenyl]carbonylamino]propyl]-2(S)-pyrrolidinecarboxamidedihydrochloride

A solution of 0.56 g (0.83.10⁻³ mol) of the compound obtained accordingto Example 34 in 4 ml of methanol is prepared and 1 ml of a saturatedsolution of hydrogen chloride in ethyl ether is added. After the mixturehas been stirred for 15 min, 50 ml of ethyl ether are added. Theprecipitate formed is filtered off, washed with ether, dried in adesiccator and then dissolved in 10 ml of water. The solution obtainedis filtered and lyophilized to give 0.58 g of the expected product inthe form of a white powder (yield=94%).

M.p.=195° C.

[α]_(D) ¹⁹ =-86° (c 0.47; CH₃ OH)

EXAMPLE 361-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[[4-(aminoiminomethyl)phenyl]carbonylamino]propyl]-2(S)-pyrrolidinecarboxamidedi(methanesulfonate)

A solution of 1.59 g (16.5.10⁻³ mol) of methanesulfonic acid in 15 ml ofmethanol is prepared and a methanol solution of 5.87 g (8.25.10⁻³ mol)of the compound obtained according to Example 5 is added slowly, withstirring. The mixture is stirred for 30 minutes at room temperature andthe solution obtained is then poured into 600 ml of ethyl ether. Thewhite precipitate formed is filtered off, washed with ether on thefilter and then dried in a desiccator under vacuum and redissolved in 50ml of water. The solution obtained is filtered and then lyophilized togive 6.6 g of the expected product in the form of a white powder(yield=88%).

M.p.=174-176° C.

[α]_(D) ²⁴ =-29° (c=0.30; CH₃ OH)

The activity of the products according to the invention was evaluated inrespect of their ability to bind to the bradykinin receptors. Kinins, ofwhich bradykinin is the main representative, actually form a group ofsmall peptides which make an important contribution to the inflammatoryresponse and therefore appear to be involved in the pathophysiology ofinflammatory diseases. Furthermore, bradykinin is one of the most potentanalgesics known. Kinins activate two types of receptor, called B₁ andB₂. The B₂ receptor belongs to the large family of receptors with seventransmembrane domains coupled to the G proteins. In the presentinvention we describe compounds which bind to the B₂ receptor andthereby block the binding of bradykinin.

The following pharmacological test is used: Ileum segments are isolatedfrom male guinea-pigs [of the Dunkin-Hartley strain (Iffa Credo,l'Arbresle, France)] and ground in the following TES buffer: TES 25 mM,1,10-phenanthroline 1 mM (pH 6.8), bacitracin 140 μg/ml, BSA 1 g/l. Themembranes are then isolated by centrifugation (18,000 rpm; 20 min; 4°C.). The binding studies are carried out in this TES buffer using [³H]-bradykinin (120 pM) and 50 μg of membrane protein per test (finalvolume 500 μl) with an equilibrium time of 90 min at 20° C. Thepercentage inhibition of the binding of [³ H]-bradykinin is thendetermined in the presence of one of the test compounds according to theinvention at a concentration of 10⁻⁶ M.

The results obtained from these tests (shown as "activity") are collatedin Table I below with reference to the Examples given in thedescription. In this Table, Pos indicates the position of the amidinegroup on the aromatic (or heteroaromatic) ring relative to the group B;in the "Salt" column, Ch1 denotes that the compound is in the form ofthe hydrochloric acid salt and Ms denotes that it is in the form of themethanesulfonic acid salt.

The compounds of the present invention which inhibit the binding of[3H]-bradykinin to the guinea-pig B₂ receptor (see Table I) also bind tothe human B₂ receptor cloned and transfected in a stable manner into CHOcells (Chinese Hamster Ovary cells). Thus, in this test, some compoundsinhibit the binding of [³ H]-bradykinin to the B₂ receptor by at least95% at a concentration of 10 μM.

The compounds of the present invention can be useful in the treatment ofpain and particularly in the treatment of numerous pathologicalconditions involving bradykinin or its homologs. These pathologicalconditions include septic and hemorrhagic shock, anaphylactic reactions,arthrosis, rheumatoid polyarthritis, rhinitis, asthma, inflammatorydiseases of the gastrointestinal tract (for example colitis, rectitis,Crohn's disease), pancreatitis, certain carcinomas, hereditaryangioedema, migraine, encephalomyelitis, meningitis, cerebrovascularcomplications (especially those caused by cerebral traumatic shock),certain neurological disorders, vascular inflammatory states (forexample atherosclerosis and arteritis of the lower limbs), painfulstates (for example headache, toothache, menstrual pain), prematureuterine contractions, cystitis and burns. The compounds according to theinvention can also be useful for the potentiation of antiviral agents.

The compounds of the present invention, which can be used in the form ofthe free base or in the form of their non-toxic addition salts inassociation with a physiologically acceptable excipient, are generallyprescribed in human therapeutics at doses of about 1 to 1000 mg/day in aform which can be administered orally, by intravenous, intramuscular orsubcutaneous injection, transdermally, by means of aerosols or by meansof suppositories.

These compounds can also be administered topically, for example in theform of a gel or ointment.

The compounds of the present invention are also useful aspharmacological reagents, especially for the study of hormone-receptorinteractions. Use as a pharmacological reagent may require aradiolabeled derivative of one of the compounds according to theinvention (for example with tritium [3H] or sulfur [³⁵ S]) in order toobtain a radioligand intended for conformational studies of thebradykinin B₂ receptor or for binding tests involving this type ofreceptor, for example for the evaluation of novel compounds which arecapable of exhibiting an affinity for the bradykinin B₂ receptor.

                                      TABLE I                                     __________________________________________________________________________                                        (I)                                                                             #STR17##                                   -                                                                                                              Acti-                                       Ex X A B R.sub.1 R.sub.2 n W Pos Salt vity                                  __________________________________________________________________________    1 Cl --NH--CO--                                                                            --     CH.sub.3                                                                         H  2 CH                                                                              4  -- --                                          2 Cl --NH--CO-- -- CH.sub.3 H 2 CH 4 Chl 92                                   3 Cl --NH--CO-- --CH.sub.2 --O-- CH.sub.3 H 2 CH 4 -- --                      4 Cl --NH--CO-- --CH.sub.2 --O-- CH.sub.3 H 2 CH 4 Chl 95.5                   5 Cl --NH--CO-- -- CH.sub.3 H 3 CH 4 -- --                                    6 Cl --NH--CO-- -- CH.sub.3 H 3 CH 4 Chl 99                                   7 Cl --NH--CO-- --CH.sub.2 -- CH.sub.3 H 3 CH 4 -- --                         8 Cl --NH--CO-- --CH.sub.2 -- CH.sub.3 H 3 CH 4 Chl 97.5                      9 Cl --NH--CO-- --CH.sub.2 --O-- CH.sub.3 H 3 CH 4 -- --                      10 Cl --NH--CO-- --CH.sub.2 --O-- CH.sub.3 H 3 CH 4 Chl 98.8                  11 Cl --NH--CO-- -- CH.sub.3 H 3 CH 3 -- --                                   12 Cl --NH--CO-- -- CH.sub.3 H 3 CH 3 Chl --                                  13 Cl --N(Et)--CO-- -- CH.sub.3 H 3 CH 4 -- --                                14 Cl --N(Et)--CO-- -- CH.sub.3 H 3 CH 4 Chl 97                               15 Cl --N(Me)--CO-- -- CH.sub.3 H 3 CH 4 -- --                                16 Cl --N(Me)--CO-- -- CH.sub.3 H 3 CH 4 Chl 100                              17 Cl --NH--CO-- -- H H 3 CH 4 -- --                                          18 Cl --NH--CO-- -- H H 3 CH 4 Chl --                                         19 Cl --NH--CO-- -- CH.sub.3 H 4 CH 4 Chl 98                                  20 Cl --NH--CO-- -- CH.sub.3 H 5 CH 4 -- --                                   21 Cl --NH--CO-- -- CH.sub.3 CH.sub.3 5 CH 4 Chl 100                          22 Cl --NH--CO-- -- CH.sub.3 CH.sub.3 3 CH 4 -- --                            23 Cl --NH--CO-- -- CH.sub.3 CH.sub.3 3 CH 4 Chl --                           24 Cl --N(Me)--CO-- -- CH.sub.3 CH.sub.3 3 CH 4 -- --                         25 Cl --N(Me)--CO-- -- CH.sub.3 CH.sub.3 3 CH 4 Chl --                        26 Cl --NH--CO-- -- CH.sub.3 H 3 N 4 -- --                                    27 Cl --NH--CO-- -- CH.sub.3 H 3 N 4 Ms --                                    28 Cl --CO--NH-- --CH.sub.2 -- CH.sub.3 H 3 CH 4  --                          29 Cl --CO--NH-- --CH.sub.2 -- CH.sub.3 H 3 CH 4 Chl --                       30 Cl --CO--NH-- -- CH.sub.3 H 3 CH 4  --                                     31 Cl --CO--NH-- -- CH.sub.3 H 3 CH 4 Chl --                                  32 Cl --NH--CO-- -- CF.sub.3 H 3 CH 4 -- --                                   33 Cl --NH--CO-- -- CF.sub.3 H 3 CH 4 Ms --                                   34 CH.sub.3 --NH--CO-- -- CH.sub.3 H 3 CH 4 -- --                             35 CH.sub.3 --NH--CO-- -- CH.sub.3 H 3 CH 4 Chl --                            36 Cl --NH--CO-- -- CH.sub.3 H 3 CH 4 Ms --                                 __________________________________________________________________________     Notes                                                                         Chl: hydrochloric acid salt                                                   Ms: methanesulfonic acid salt                                                 Pos: position of the amidine group relative to B [the amidine group of Ex     26 and Ex. 27 is in the 5position on the pyridinyl ring (W = N)]-        

What is claimed is:
 1. An N-(benzenesulfonyl)-L-proline compoundselected from the group consisting of:(i) formula I: ##STR18## in which:X is a halogen atom or a methyl group,A is a group --N(R₃)--CO-- or--CO--N(R₃)--, B is a s ingle bond, --CH₂ -- or --CH₂ --O--, R₁ is ahydrogen atom a C₁ -C₃ alkyl group or a trifluoromethyl group, R₂ and R₃are each independently a hydrogen atom or a C₁ -C₃ alkyl group,W is CHor N, and n is 2, 3, 4 or 5; and (ii) their addition salts.
 2. Acompound according to claim 1 wherein X is Cl.
 3. A process for thepreparation of a compound of formula I, said process comprising:(1)reacting an acid of formula II: ##STR19## in which: R₁ is a hydrogenatom, a C₁ -C₃ alkyl group or a trifluoromethyl group, andX is a halogenor a methyl group, with an amine of formula III: ##STR20## in which: R₂and R₃ are each independently H or a C₁ -C₃ alkyl group,n is 2, 3, 4 or5, and Y is an amino-protecting group, in a solvent, in the presence ofat least one activator commonly used to create linkages of the peptidetype, at a temperature between about 0 and about 40° C., for 2 to 50hours, to give a compound of formula IV: ##STR21## in which R₁, R₂, R₃,X, Y and n are as defined above; (2) deprotecting the resulting compoundof formula IV to replace the protecting group Y with a hydrogen atom, ina solvent, at a temperature of 0-40° C., for 5 to 30 hours, to give thecompound of formula V: ##STR22## in which R₁, R₂, R₃, X and n are asdefined above; (3) reacting the resulting compound of formula V with anacid of formula VI: ##STR23## in which: B is a single bond or a group--CH₂ -- or --CH₂ --O--, andW is --CH-- or a nitrogen atom, underconditions analogous to those recommended for step (1), and, ifnecessary, in the presence of a base if the amine of formula V isreacted in its salified form, to give the compound of formula I:##STR24## in which: A is --N(R₃)--CO--,B is a single bond, --CH₂ -- or--CH₂ --O--, R₁ is H, a C₁ -C₃ alkyl group or a trifluoromethyl group,R₂ and R₃ are each independently H or a C₁ -C₃ alkyl group, X is ahalogen atom or a methyl group, W is CH or N, and n is 2, 3, 4 or 5; and(4) if necessary, reacting the resulting compound of formula I, in theform of the base, with a mineral or organic acid to give said compoundof formula I in the form of an addition salt.
 4. A process for thepreparation of a compound of formula I according to claim 3, saidprocess comprising:(a) reacting the compound of formula V, obtained instep (2), with a compound of formula VIII: ##STR25## in which: B is asingle bond, --CH₂ -- or --CH₂ O--, andW is CH or N, under operatingconditions analogous to those of step (3), to give a compound of formulaIX: ##STR26## in which R₁, R₂, R₃, X, W, n and B are as defined in thestarting materials;(b) reacting the resulting compound of formula IXwith hydroxylamine, in a solvent, at a temperature of 0-40° C., for 2 to12 hours, to give the compound of formula X: ##STR27## in which R₁, R₂,R₃, X, W, n and B are as defined above; (c) reacting the resultingcompound of formula X with excess acetic anhydride in a solvent, at atemperature of 0-40° C., for 1 to 15 hours, to give the compound offormula XI: ##STR28## in which R₁, R₂, R₃, X, W, n and B are as definedabove; (d) catalytically hydrogenating the resulting compound of formulaXI in a solvent, in the presence of a hydrogenation catalyst, at atemperature of 0-40° C., under a hydrogen pressure of between 10⁵ and5.10⁵ Pa, to give the compound of formula I in which R₁, R₂, R₃, X, W, nand B are as defined above, A is the group --N(R₃)--CO-- and the amidinegroup retains the initial position of the cyano group of the startingacid; and (e) if necessary, reacting the resulting compound of formulaI, in the form of the base, with a mineral or organic acid to give saidcompound of formula I in the form of an addition salt.
 5. A processaccording to claim 3 wherein, in step (3), (i) the acid of formula VI isreplaced with the corresponding acid chloride, and (ii) the reaction iscarried out in a solvent in the presence of an aprotic base.
 6. Atherapeutic composition containing, in association with aphysiologically acceptable excipient, at least one compound selectedfrom the group consisting of a compound of formula I and their non-toxicacid addition salts according to claim
 1. 7. A method of treating apathological condition involving bradykinin or its homolog comprisingadministering an effective amount of a bradykinin B₂ receptor antagonistselected from the group consisting of the compounds of formula I andtheir non-toxic addition salts according to claim
 1. 8. A methodaccording to claim 7 wherein said pathological condition involvingbradykinin or its homologs is pain.
 9. A method according to claim 7wherein said pathological condition involving bradykinin or its homologsis inflammation.
 10. A method of studying hormone-bradykinininteractions comprising binding a compound of formula I or one of itsacid addition salts according to claim 1 to a bradykinin B₂ receptor.11. The process of claim 3, wherein in the reaction of step (1) iscarried out at a temperature of between 10 and 35° C.
 12. The process ofclaim 3, wherein in the reaction of step (2) is carried out at atemperature of between 15 and 25°C.